RESUMEN
Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies.
Asunto(s)
Benzamidas , Compuestos de Bifenilo , Interacciones Farmacológicas , Morfolinas , Humanos , Morfolinas/farmacocinética , Morfolinas/farmacología , Morfolinas/administración & dosificación , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/administración & dosificación , Piridonas/farmacocinética , Piridonas/farmacología , Piridonas/administración & dosificación , Piridonas/uso terapéutico , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Sulfonamidas/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Animales , Organofosfatos/farmacocinética , Organofosfatos/farmacologíaRESUMEN
INTRODUCTION: Tazemetostat is an enhancer of zeste homolog 2 (EZH2) inhibitor recommended for patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type or mutant EZH2. The phosphoinositide 3-kinase (PI3K) inhibitors idelalisib, copanlisib, umbralisib and (formerly) duvelisib are indicated for third-line, fourth-line, and later (3L/4L+) treatment of R/R FL. The objective of this analysis was to provide an indirect treatment comparison of tazemetostat with each PI3K inhibitor for 3L/4L+ R/R FL treatment. METHODS: A systematic literature review was conducted to identify trials for idelalisib (DELTA), duvelisib (DYNAMO), copanlisib (CHRONOS-1 Part B), and umbralisib (UNITY-NHL) in 3L+ R/R FL. Matching-adjusted indirect comparisons were conducted by weighting tazemetostat individual patient data with available baseline characteristics from each comparator trial: age, Eastern Cooperative Oncology Group performance status, disease stage, histology, prior treatment lines, prior stem cell therapy, progression within 24 months, and refractory status to last therapy. Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Primary safety outcomes included risk of grade ≥ 3 treatment-emergent adverse events (TEAEs); primary efficacy outcomes included objective response rate (ORR). RESULTS: Matched patients treated with tazemetostat had lower relative risk (RR) for all grouped safety outcomes, including any grade ≥ 3 TEAEs, compared with idelalisib (RR = 0.45), duvelisib (RR = 0.35), copanlisib (RR = 0.37), and umbralisib (RR = 0.65; all, p < 0.01), any serious TEAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. The ORR was not significantly different for tazemetostat versus other treatments (idelalisib 43% vs 56%, p = 0.16; duvelisib 48% vs 47%, p = 0.91; copanlisib 49% vs 61%, p = 0.11; and umbralisib 57% vs 47%, p = 0.10). CONCLUSIONS: In this statistically adjusted comparison, tazemetostat was associated with lower RR for safety outcomes versus idelalisib, duvelisib, copanlisib, and umbralisib, while achieving similar efficacy outcomes.
Asunto(s)
Linfoma Folicular , Fosfatidilinositol 3-Quinasas , Benzamidas , Compuestos de Bifenilo , Preescolar , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Isoquinolinas , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/genética , Linfoma Folicular/patología , Morfolinas , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/uso terapéutico , Purinas , Piridonas , Pirimidinas , Quinazolinas , Quinazolinonas , RiesgoRESUMEN
BACKGROUND: Cancer is spreading all over the world, and it is becoming the leading cause of major deaths. Today's most difficult task for every researcher is to invent a new drug that can treat cancer with minimal side effects. Many factors, including pollution, modern lifestyle and food habits, exposure to oncogenic agents or radiations, enhanced industrialization, etc. can cause cancer. Treatment of cancer is done by various methods that include chemotherapy, radiotherapy, surgery and immunotherapy in combination or singly along with kinase inhibitors. Most of the anti-cancer drugs use the concept of kinase inhibition. OBJECTIVE: The number of drugs being used in chemotherapy has heterocycles as their basic structure in spite of various side effects. Medicinal chemists are focusing on nitrogen-containing heterocyclic compounds like pyrrole, pyrrolidine, pyridine, imidazole, pyrimidines, pyrazole, indole, quinoline, oxadiazole, azole, benzimidazole, etc. as the key building blocks to develop active biological compounds. The aim of this study is to attempt to compile a dataset of nitrogen-containing heterocyclic anti-cancer drugs. METHODS: We adopted a structural search on notorious journal publication websites and electronic databases such as Bentham Science, Science Direct, PubMed, Scopus, USFDA, etc. for the collection of peer-reviewed research and review articles for the present review. The quality papers were retrieved, studied, categorized into different sections, analyzed and used for article writing. CONCLUSION: As per FDA databases, nitrogen-based heterocycles in the drug design are almost 60% of unique small-molecule drugs. Some of the nitrogen-containing heterocyclic anti-cancer drugs are Axitinib, Bosutinib, Cediranib, Dasatanib (Sprycel®), Erlotinib (Tarceva®), Gefitinib (Iressa®), Imatinib (Gleevec®), Lapatinib (Tykerb ®), Linifanib, Sorafenib (Nexavar®), Sunitinib (Sutent®), Tivozanib, etc. In the present review, we shall focus on the overview of nitrogen-containing heterocyclic active compounds as anti-cancer agents.